WO2021036953A1 - Composé phénylpyrrolidine - Google Patents

Composé phénylpyrrolidine Download PDF

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WO2021036953A1
WO2021036953A1 PCT/CN2020/110622 CN2020110622W WO2021036953A1 WO 2021036953 A1 WO2021036953 A1 WO 2021036953A1 CN 2020110622 W CN2020110622 W CN 2020110622W WO 2021036953 A1 WO2021036953 A1 WO 2021036953A1
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group
diseases
compound
pde4
membered
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Chinese (zh)
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张学军
李莉娥
沈洁
付强强
孙红娜
叶大炳
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湖北生物医药产业技术研究院有限公司
人福医药集团股份公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a novel phenylpyrrolidine compound, its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, its preparation method, and pharmaceutical compositions containing them as well as PDE4 inhibitors
  • the purpose of the agent is to a novel phenylpyrrolidine compound, its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, its preparation method, and pharmaceutical compositions containing them as well as PDE4 inhibitors The purpose of the agent.
  • Phosphodiesterase (abbreviated as PDE), or more precisely 3', 5'-cyclic nucleotide phosphodiesterase, is the second messenger cAMP (cyclic adenosine acid) and cGMP (cyclic guanosine acid) Hydrolysis to 5'-AMP (5'-adenosine monophosphate) and 5'-GMP (5'-guanosine monophosphate) enzymes.
  • PDE4 is the most important regulator of cAMP expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (Z.
  • PDE4 can regulate the inflammation of inflammatory cells by regulating pro-inflammatory cytokines (such as TNF ⁇ , IL-2, IFN- ⁇ , GM-CSF and LTB4) reaction. Inhibition of PDE4 can effectively treat asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, inflammatory bowel diseases such as Crohn's disease (Crohn's disease), atopic dermatitis (AD) and other inflammations Sexual disease.
  • COPD chronic obstructive pulmonary disease
  • rheumatoid arthritis rheumatoid arthritis
  • atopic dermatitis inflammatory bowel diseases such as Crohn's disease (Crohn's disease)
  • AD atopic dermatitis
  • PDE4 includes PDE4A, PDE4B, PDE4C, PDE4D and other subtypes. Inhibition of PDE4D can cause side effects such as vomiting, and selective inhibition of PDE4B can improve the occurrence of side effects of vomiting (Osamu Suzuki et al., J Pharmacol Sci 123, 219-226, 2013).
  • cyclic nucleotides are important second messengers for regulating smooth muscle contractility.
  • Cyclic nucleotide phosphodiesterase (PDE) hydrolyzes cyclic nucleotides and is important in regulating the level of cyclic nucleotides in cells and the duration of action. Compounds that inhibit PDE increase the cellular level of cyclic nucleotides, thereby relaxing many types of smooth muscle. Studies have shown that phosphodiesterase 4 (PDE4) can specifically hydrolyze cAMP, and it is abundantly expressed in the bladder.
  • PCT patent application WO2016040083A1 discloses some azetidinyloxyphenylpyrrolidine compounds, which can be used as PDE4 inhibitors to treat overactive bladder (OAB) and related symptoms, such as frequent urination and urgency, and others Alleviation of illness.
  • OAB overactive bladder
  • the inventors of the present invention have synthesized a novel compound that can inhibit the activity of PDE4B and PDE4D.
  • the compound can be used to prepare PDE4 inhibitors with novel structure, excellent efficacy, high bioavailability, and good druggability.
  • PDE4 inhibitors can be used to inhibit the activity of PDE4 and up-regulate the level of cAMP in immune and inflammatory cells, thereby Reduce the release of pro-inflammatory cytokines, which in turn reduces the inflammatory response.
  • the compounds provided by the present invention can effectively treat diseases and disorders related to PDE4, including but not limited to inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritis diseases, skin inflammatory diseases, inflammatory diseases Intestinal diseases and diseases related to smooth muscle contractility.
  • the present invention provides a compound which is a compound represented by general formula (A-1) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or a compound represented by general formula (A-1) Prodrug:
  • R 1 is selected H, unsubstituted or optionally substituted by at least one R a group of the following: C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 6 - C 20 aryl, 5-20 membered heteroaryl;
  • Each of said at least one of R a same or different and are independently selected from F, Cl, Br, I, OH, CN, O, NO 2, unsubstituted or optionally substituted by at least one R b is a group of the following Group: -NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 6 -C 20 aryl, C 6 -C 20 aryloxy, 5-20 membered hetero Aryl, 5-20 membered heteroaryloxy;
  • R 2 is selected from the following groups H, unsubstituted or optionally substituted with at least one R c : C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic group, C 6- C 20 aryl, 5-20 membered heteroaryl;
  • R 1 is not methyl, ethyl, or isopropyl.
  • the inventors through a large number of experimental explorations, synthesized a new type of compound of general formula (A-1), and found that the compound can inhibit the activity of PDE4 subtypes PDE4D and PDE4B. Since PDE4 can specifically hydrolyze cAMP in cells, the compounds of the present invention can increase the level of cAMP in immune and inflammatory cells by inhibiting the activity of PDE4, thereby reducing pro-inflammatory cytokines (such as TNF ⁇ , IL-2, The release of IFN- ⁇ , GM-CSF and LTB4, etc.), which in turn reduces the inflammatory response.
  • pro-inflammatory cytokines such as TNF ⁇ , IL-2, The release of IFN- ⁇ , GM-CSF and LTB4, etc.
  • the compounds of the present invention can be used to regulate the level and duration of action of cAMP in cells by inhibiting the activity of PDE4, and then relax various types of smooth muscle.
  • the compound of the general formula (A-1) of the present invention can be used to treat diseases and disorders related to PDE4, including but not limited to inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritis Diseases, skin inflammatory diseases, inflammatory bowel disease, and diseases related to smooth muscle contractility.
  • the present invention provides a compound represented by general formula (A), its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
  • R 1 is selected from H, unsubstituted or optionally substituted with one or more substituents R a following groups: C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 20 aryl, 5-20 membered heteroaryl;
  • R 1 is not methyl, ethyl, or isopropyl.
  • R 1 is selected from a C 1 -C 10 alkyl group that is unsubstituted or optionally substituted with at least one Ra , C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 10 alkyl, C 3- C 10 cycloalkyl, 3-10 membered heterocyclic group;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 10 alkyl, C 3- C 10 cycloalkyl;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 5 alkyl, C 3- C 5 cycloalkyl;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 5 alkyl, C 3- C 5 cycloalkyl;
  • Each of the at least one R c is the same or different and is independently selected from F, Cl, Br, and I, respectively.
  • the compound is selected from one of the following structures:
  • novel compounds provided by the present invention can inhibit the activity of PDE4 subtypes PDE4B and PDE4D.
  • inhibition of PDE4D can cause side effects such as vomiting
  • compounds 001, 003, 004, 005 and 006 can selectively inhibit the activity of PDE4B, thereby effectively improving the occurrence of side effects such as vomiting.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (A-1) and/or (A) or its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers, diluents or excipients.
  • the compounds provided by the present invention are used to prepare drugs in various dosage forms, which are administered to subjects in a therapeutically effective amount. After the drugs are absorbed by the subjects, they can increase intracellular cAMP levels, thereby affecting the pro-inflammatory cytokine levels. Release and smooth muscle state, thereby treating or ameliorating diseases related to PDE4.
  • the pharmaceutical composition further comprises one or more other therapeutic agents.
  • the other therapeutic agents have similar functions to the compounds of the present invention, and can be used to treat diseases related to PDE4.
  • the present invention relates to suitable pharmaceutically acceptable salts of compounds represented by general formula (A-1) or (A), including but not limited to hydrochloride, hydrobromide, sulfate or hydrogen sulfate, phosphate or Hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate Acid salt or p-toluenesulfonate.
  • any of the compounds of the present invention mentioned herein include pharmaceutically acceptable salts, solvates, or combinations thereof.
  • the present invention also includes other salts. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used in the identification, characterization or purification of the compounds of the present invention.
  • the present invention relates to the compound represented by the general formula (A-1) or (A), its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, in the preparation of therapeutics and phosphodiesterase -4 (PDE4) Use in medicines related to diseases.
  • the disease related to phosphodiesterase-4 is selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritic diseases, skin inflammatory diseases, Inflammatory bowel disease and diseases related to smooth muscle contractility.
  • the allergic disease is selected from asthma, chronic bronchitis, chronic obstructive pneumonia, allergic rhinitis, adult respiratory distress syndrome.
  • the skin inflammatory disease is selected from idiopathic dermatitis, psoriasis or urticaria.
  • the arthritis disease is selected from rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis.
  • the inflammatory bowel disease is selected from ulcerative colitis or Crohn's disease.
  • the disease related to smooth muscle contractility is selected from overactive bladder and related symptoms, such as frequent urination and urgency.
  • the present invention also provides the use of the compound represented by the general formula (A-1) or (A), its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, and prodrugs in the treatment of diseases related to PDE4.
  • the diseases related to PDE4 are selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritic diseases, skin inflammatory diseases, inflammatory bowel diseases, and Diseases related to smooth muscle contractility.
  • the diseases related to PDE4 are selected from asthma, chronic bronchitis, chronic obstructive pneumonia, allergic rhinitis, adult respiratory distress syndrome, idiopathic dermatitis, psoriasis, urticaria, Rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis, ulcerative colitis, Crohn’s disease, overactive bladder.
  • the present invention also provides a method for treating diseases related to PDE4 by administering the pharmaceutical composition to patients suffering from diseases related to PDE4.
  • the diseases related to PDE4 are selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritic diseases, skin inflammatory diseases, inflammatory bowel diseases, and Diseases related to smooth muscle contractility.
  • the diseases related to PDE4 are selected from asthma, chronic bronchitis, chronic obstructive pneumonia, allergic rhinitis, adult respiratory distress syndrome, idiopathic dermatitis, psoriasis, urticaria, Rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis, ulcerative colitis, Crohn’s disease, overactive bladder.
  • the present invention also relates to a method for treating diseases related to phosphodiesterase-4 (PDE4), which comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation containing the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • PDE4 phosphodiesterase-4
  • salts derived from inorganic bases include, but are not limited to, metal salts formed by Al, Ca, Li, Mg, K, Na, and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary or tertiary amines, including Naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins, such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, Dimethylethanolamine, 2-Dimethylaminoethanol, 2-Diethylaminoethanol, Dicyclohexylamine, Caffeine, Procaine, Choline, Betaine, Benminicillin, Ethylenediamine, Glucosamine, Organic salts
  • stereoisomer refers to the isomers produced by the different arrangements of atoms in the molecule in space, including cis and trans isomers, enantiomers, diastereomers and conformational isomers.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more mutually convertible species.
  • Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in an equilibrium form. An attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule.
  • the ketone type is dominant; in phenol, the enol type is dominant.
  • the present invention encompasses all tautomeric forms of the compound.
  • pharmaceutical composition means a mixture of one or more of the compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable Carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the compound to the organism, which is conducive to the absorption of the active ingredient and thus the biological activity.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the functional group in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • Prodrugs include compounds formed by connecting a hydroxyl group or amino group to any group in the compound of the present invention. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form a free hydroxyl group and a free group, respectively. The amino group.
  • C 1 -C 10 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-d
  • C 2 -C 10 alkynyl should be understood to preferably mean a linear or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 Or 10 carbon atoms.
  • C 3 -C 10 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3-10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as decalin ring.
  • C 3 -C 6 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which has 3 to 6 carbon atoms.
  • heterocyclic group means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or a 7-membered ring, such as diazacycloheptanyl.
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • C 6 -C 20 aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-20 carbon atoms.
  • a ring having 6 carbon atoms such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or having 10
  • a ring with three carbon atoms such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or a ring with 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or Is a ring with 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 20 aryloxy group means that it is connected to at least one oxy group "-O-" on the basis of the aforementioned "C 6 -C 20 aryl group”.
  • 5-20 membered heteroaryl should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5-20 ring atoms and containing 1-5 independently selected from N, O And S heteroatoms, for example "5-14 membered heteroaryl”.
  • the term “5-14 membered heteroaryl” should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms each independently selected from the group consisting of N, O and S, in addition in each case Can be benzo-fused.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, thio-4H-pyrazolyl, etc.
  • 5-20 membered heteroaryloxy group refers to the connection with at least one oxy group "-O-" on the basis of the aforementioned "5-20 membered heteroaryl group”.
  • excipients refers to pharmaceutically acceptable inert ingredients.
  • Non-limiting examples of the types of the term “excipient” include binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical preparation, that is, make the preparation more suitable for direct compression by increasing fluidity and/or adhesion.
  • Examples of typical "pharmaceutically acceptable carriers” suitable for the above formulations are: sugars, such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch, and potato starch; cellulose and its derivatives Substances, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid ; Alkaline earth metal stearates, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants ; Glycol polymers; fatty alcohols; and grain hydrolyzed solids and other non-toxic compatible fillers
  • the present invention also relates to a method for preparing the compound of general formula (A) of the present invention, which method comprises:
  • R 1 is defined as described above;
  • X is halogen, such as Cl, Br, I, etc.;
  • the structure of formula (IV) is Wherein, the compound of formula (I) is coupled with azetidin-3-ol or its salt under catalyst conditions to obtain the compound of formula (II); the compound of formula (II) is reacted with methylsulfonyl chloride to obtain the compound of formula (III) ) Compound, the compound of formula (III) further undergoes a nucleophilic substitution reaction with the compound of formula (IV) to obtain the compound of formula (V), and the compound of formula (V) removes the protective agent under acidic conditions to obtain the target compound (A).
  • the synthetic route and preparation method of formula (IV) refer to the synthetic methods disclosed in patent applications WO2001047905A1, CN106795137A and the journal documents Nichols, P.J.; DeMattei, J.A. Org. Lett. 2006, 8, 1495-1498.
  • the synthetic route and preparation method of the compound of general formula (A-1) provided by the present invention are similar to the aforementioned method of preparing the compound of general formula (A), except that the starting materials during synthesis are different, that is, the above-mentioned formula (I) The compounds are different.
  • Figure 1 shows the clinical scores of the G1, G2, G3 and G4 groups in the mouse CIA arthritis model experiment
  • Figure 2 shows the AUC inhibition rate of the clinical scores in the G2, G3 and G4 groups in the mouse CIA arthritis model experiment.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • N equivalent concentration, for example, 1N hydrochloric acid means 1mol/L hydrochloric acid solution
  • PE Petroleum ether
  • Ms methylsulfonyl
  • LPS Lipopolysaccharide, lipopolysaccharide (endotoxin)
  • PBMC peripheral blood mononuclear cells
  • TNF ⁇ tumor necrosis factor ⁇
  • PBS phosphate buffered saline
  • FBS fetal bovine serum
  • IC 50 The half inhibition concentration refers to the concentration at which half of the maximum inhibition effect is reached.
  • the third step ((3S,4S)-4-(3-((1-(5-cyclopropoxypyridin-2-yl)azetidinyl)oxy)-4-methoxyphenyl)- 3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl)((S)-2,2-dimethyl-1,3-dioxolane-4 -Yl) ketone (001D) synthesis
  • the fourth step (S)-1-((3S,4S)-4-(3-((1-(5-cyclopropoxypyridin-2-yl)azetidin-3-yl)oxy )-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)3-methylpyrrolidin-1-yl)-2,3-dihydroxypropane-1-one (target compound 001 ) Synthesis (target compound 001) synthesis
  • Dibromohydantoin (50.5g, 176.4mmol) was added to 300mL DCM at room temperature, cooled to -78°C, 70% pyridine hydrofluoric acid solution (400mL, 3136.8mmol) was added at low temperature, and stirred for 45min. Slowly drip O-(6-bromo-2-methylpyridin-3-yl) methyl mercaptothiocarbonate (005C) (10.9g, 39.2mmol) in 100mL DCM solution, and slowly warm up to -5 after dripping °C, stir for 1.5h.
  • Step 5 Synthesis of 1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidine-3-yl methanesulfonate (005F)
  • the sixth step ((S)-2,2-dimethyl-1,3-dioxolane-4-yl)((3S,4S)-3-((R)-1-hydroxyethyl Yl)-4-(4-methoxy-3-((1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy (Yl)phenyl)-3-methylpyrrolidin-1-yl)methanone (005G)
  • the seventh step (S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-( (1-(6-Methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidine-1- Base) synthesis of propan-1-one (005)
  • Dibromohydantoin (37.0g, 129.5mmol) was added to 300mL DCM at room temperature, cooled to -78°C, 60% pyridine hydrofluoric acid solution (368mL, 2473.6mmol) was added at low temperature, and stirred for 45min. Slowly drip O-(6-bromo-4-methylpyridin-3-yl) S-methyl dithiocarbonate (006C) (8.0g, 28.7mmol) in 100mL DCM solution, and slowly heat up after dripping To -5°C, stir for 1.5h.
  • Step 5 Synthesis of 1-(4-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl methanesulfonate (006F)
  • the seventh step (S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-( (1-(4-Methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl ) Synthesis of propan-1-one (006)
  • the inhibitory activity of the positive control compound and the compounds 001-006 provided by the present invention on PDE4B and PDE4D can be detected by using the PDE-Glo Phosphodiesterase Assay Kit (promega, V1361). To put it simply, first prepare a 10mM concentrated stock solution of the compound to be tested in DMSO solvent, and then dilute it into a 10 ⁇ working solution with the Reaction buffer provided by the kit. Operate on ice, use Reaction buffer to dilute PDE4B enzyme (Enzo Life Sciences, BML-SE522-0020) to a concentration of 1ng/ ⁇ L, and PDE4D enzyme (Enzo Life Sciences, BML-SE523-0020) to a concentration of 4ng/ ⁇ L .
  • Table 1 shows the inhibitory activity of the positive control compound, the compounds 001 to 006 provided by the present invention, on PDE4B and PDE4D determined by the enzyme activity experiment.
  • Example 8 LPS induces human PBMC to secrete TNF ⁇ model test
  • PBMC extraction process obtain fresh human peripheral blood concentrate, draw 1 unit of human peripheral blood concentrate (concentrated from 200cc peripheral blood), add 0.9% normal saline to a total volume of 120ml, and mix well. Take a 50ml centrifuge tube, add 15ml Lymphoprep TM separately , hold the centrifuge tube at an angle of about 45 degrees, draw 30ml of the diluted concentrated blood, carefully and slowly adhere to the wall, so that the diluted blood overlaps the layering solution, avoiding dilution The blood mixes into the separation liquid or breaks through the liquid surface of the separation liquid. The ratio of Lymphoprep TM to diluted blood is 1:2.
  • centrifuge tube Place the centrifuge tube in a horizontal centrifuge (eppendorf, 5810R), and centrifuge at 800g for 20 minutes at 20°C, with the rising speed set to 1, and the falling speed set to 0. Carefully remove the centrifuge tube. Directly insert the Pasteur pipette deep into the albuginea layer to absorb PBMC. Add 3 times the volume of 0.9% saline or PBS (without calcium and magnesium), gently pipetting to mix. After mixing, centrifuge at 250g for 10 min at 20°C to remove the platelets remaining in the cell suspension, remove the supernatant, and suspend the cell pellet in 20ml PBS, and count by trypan blue staining.
  • PBMC screening process Centrifuge the PBMC obtained in step 1, remove PBS, and then resuspend the count in complete medium (RPMI1640+10%FBS+1%P/S). The cells were inserted at 5 ⁇ 10 4/ well and 100 ⁇ L/well. The compound to be screened is formulated to 4 ⁇ at the final concentration. Add 50 ⁇ L/well to the cells. Pre-incubate for 30 minutes in advance. At the same time, set a control well without adding compound. The final concentration of LPS for stimulation is 10ng/ml, prepared as 4 ⁇ , and added to the cells at 50 ⁇ l/well. At the same time, set the control wells without adding LPS wells. Continue to incubate the cells and collect 10% supernatant for detection at 24h. The collected supernatant was tested according to Invitrogen's Human TNF ⁇ kit (REF: 88-7346-88).
  • the inhibitory activity of the positive control compound, the compounds 001 to 006 provided by the present invention, on LPS-induced TNF ⁇ secretion from human PBMC was determined according to the above method.
  • Test compound IC 50 (nM) Positive control group 3.32 001 0.96 002 1.45 003 1.67 004 5.32 005 0.63 006 0.50
  • the experimental results show that, compared with the positive control group, the compounds 001 ⁇ 003 and 005, 006 of the present invention have better inhibitory activity of human PBMC secreting TNF ⁇ , can better inhibit the secretion of inflammatory factor TNF ⁇ in human PBMC, and have more prominent The anti-inflammatory effect.
  • Compound 004 has an inhibitory activity on the secretion of TNF ⁇ from human PBMC, which is equivalent to that of the positive control group, and can also inhibit the secretion of the inflammatory factor TNF ⁇ in human PBMC, and has an anti-inflammatory effect.
  • mice Take 18 Balb/c mice, age: 6-8 weeks, randomly assigned to blank group, model group and administration group, orally orally give vehicle (blank group, model group) or 50mg/kg compound (given The drug group, the positive control group was given a dose of 100 mg/kg).
  • vehicle the positive control group was given a dose of 100 mg/kg.
  • PBS blank group
  • 1 mg/kg LPS model group and administration group
  • the mouse TNF ⁇ detection kit (Mouse TNF ⁇ ELISA kit: Biolegend, Cat: 430904) was used to detect the serum TNF ⁇ level.
  • the compound's release inhibitory activity on TNF ⁇ was calculated based on the serum TNF ⁇ level.
  • Compound inhibitory activity % ⁇ 1-(administration group TNF ⁇ concentration-blank group TNF ⁇ concentration)/(model group TNF ⁇ concentration-blank group TNF ⁇ concentration) ⁇ 100
  • mice 9 male CD-1 mice, 20-25g, fasted overnight, orally administered 10 mg/kg by gavage. Three mice were taken at each time point of blood collection, and a total of 9 mice were taken alternately before the administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after the administration. The blood sample was centrifuged at 8000 rpm for 6 minutes at 4°C, and the plasma was collected and stored at -20°C.
  • the experimental results showed that, compared with the compounds in the positive control group, the compounds 001 and 002 of the present invention showed better plasma exposure. Both Cmax and AUC0-t were better than those in the positive control group. Cmax was about twice that of the positive control group. The exposure amount AUC0-t is about 3 times that of the positive control; the compound of the present invention has excellent pharmacokinetic properties.
  • acetic acid Dilute 2N acetic acid to 100mM, filter with 0.22 micron filter membrane, and store at 4°C.
  • bovine type II collagen solution dissolve bovine type II collagen (CII) in 100 mM acetic acid solution and store at 4°C overnight. The final concentration of collagen is 8 mg/mL.
  • Preparation of emulsion Mix the CII solution stored overnight with an equal volume of complete Freund's adjuvant, use a high-speed homogenizer, and homogenize on ice at 30,000 revolutions per minute for approximately 60 minutes, until the solution forms a stable emulsion.
  • mice induced by arthritis were randomly grouped according to their body weight, so that the average body weight of each group was consistent, and they were randomly divided into 4 treatment groups for administration, with 10 mice in each group.
  • G1 is a normal mouse without any treatment; G2 group was given a blank vehicle; G3 and G4 groups were given a compound (positive control compound and compound 002), at a dose of 30 mg/kg, twice a day for a total of 21 days.
  • the volume of intragastric administration is 10 mL/kg.
  • the mice After boosting the immunity, observe the mouse disease every day.
  • the clinical score is based on the different degree of the disease (redness, joint deformation) according to the standard of 0-4 points, the highest score for each limb is 4 points, and each animal The maximum score is 16 points. Score at least three times a week.
  • Inhibition rate% 1-(administration group AUC/blank vehicle group AUC)*100%
  • the experimental data is expressed by Mean ⁇ SEM, and the clinical score is expressed by One-way ANOVA. P ⁇ 0.05 is considered as a significant difference.
  • Figure 1 and Figure 2 show the results of the clinical score and the AUC inhibition rate of the clinical score for each group
  • Table 6 shows the results of the clinical score and the AUC inhibition rate of the clinical score at the end of the experiment.

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Abstract

La présente invention concerne un composé phénylpyrrolidine, c'est-à-dire un composé représenté par la formule générale (A-1) ou (A), permettant d'obtenir un inhibiteur de PDE4 ayant une nouvelle structure, un bon effet médical, une biodisponibilité élevée et une bonne pharmacopotentialité, et utilisé pour traiter de manière efficace des maladies et des troubles liés à PDE4, y compris, mais sans s'y limiter, les maladies inflammatoires, les maladies allergiques, les maladies auto-immunes, le rejet de greffe, les maladies inflammatoires articulaires, les maladies inflammatoires cutanées, les maladies intestinales inflammatoires et les maladies liées à la contraction des muscles lisses, etc. (A-1) (A)
PCT/CN2020/110622 2019-08-23 2020-08-21 Composé phénylpyrrolidine WO2021036953A1 (fr)

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CN105051034A (zh) * 2013-03-13 2015-11-11 伊莱利利公司 氮杂环丁烷基氧基苯基吡咯烷化合物
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CN107001327A (zh) * 2014-09-04 2017-08-01 伊莱利利公司 晶体(2s)‑3‑[(3s,4s)‑3‑[(1r)‑1‑羟乙基]‑4‑(4‑甲氧基‑3‑{[1‑(5‑甲基吡啶‑2‑基)氮杂环丁‑3‑基]氧基}苯基)‑3‑甲基吡咯烷‑1‑基]‑3‑氧代丙烷‑1,2‑二醇
CN111333626A (zh) * 2018-12-18 2020-06-26 湖北生物医药产业技术研究院有限公司 苯基吡咯烷类化合物及其用途
CN111333637A (zh) * 2018-12-18 2020-06-26 湖北生物医药产业技术研究院有限公司 苯基吡咯烷类衍生物及其制备方法
CN111333625A (zh) * 2018-12-18 2020-06-26 湖北生物医药产业技术研究院有限公司 苯基吡咯烷类化合物及其用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1434813A (zh) * 1999-12-23 2003-08-06 艾科斯有限公司 作为环腺苷酸－特异性磷酸二酯酶抑制剂的吡咯烷衍生物
CN105051034A (zh) * 2013-03-13 2015-11-11 伊莱利利公司 氮杂环丁烷基氧基苯基吡咯烷化合物
CN107001327A (zh) * 2014-09-04 2017-08-01 伊莱利利公司 晶体(2s)‑3‑[(3s,4s)‑3‑[(1r)‑1‑羟乙基]‑4‑(4‑甲氧基‑3‑{[1‑(5‑甲基吡啶‑2‑基)氮杂环丁‑3‑基]氧基}苯基)‑3‑甲基吡咯烷‑1‑基]‑3‑氧代丙烷‑1,2‑二醇
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CN111333625A (zh) * 2018-12-18 2020-06-26 湖北生物医药产业技术研究院有限公司 苯基吡咯烷类化合物及其用途

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